Process for the methylenation of catechols

ABSTRACT

A method for the methylenation of catechols via the reaction of catechols with methylene chloride in the presence of selected strong bases is described. This process has wide applicability in the field of synthetic organic chemistry, especially in natural product syntheses.

United States Patent [1 1 Leimgruber et al.

[ Nov. 25, 1975 I PROCESS FOR THE METHYLENATION OF CATECHOLS [75]Inventors: Willy Leimgruber, Montclair, N..l.;

Alexander E. Wick, Riehen,

Switzerland [73] Assignee: Hoffmann-La Roche Inc., Nutley,

[22] Filed: Dec. 6, 1972 [211 App]. No.: 312,468

Related US. Application Data [62] Division of Ser. No. 128,572, March26, 1971, Pat.

[52] US. Cl 260/3405; 260/293.63; 260/289 R;

260/326.85; 260/583 P [51] Int. 01. c071) 317/54 [58] Field of Search260/3405 [56] References Cited UNITED STATES PATENTS 3,436,403 4/1969Cornforth 260/3405 X 3,790,601 2/1974 Gallay 260/3405 OTHER PUBLICATIONSWeingarten et al., Journ. Amer. chem. Soc," Vol. 88 (4), 1966, p. 850.

Primary ExaminerDonald G. Daus Assistant Examiner.l. H. TurnipseedAttorney, Agent, or Firm-Samuel L. Welt; Bernard S. Leon; Frank P.Hoffman [57] ABSTRACT 2 Claims, No Drawings PROCESS FOR THEMETHYLENATION or CATECHOLS CROSS-REFERENCE TO RELATED APPLICATIONS IThis application is a divisional application of copending applicationSer. No. 128,572, filed Mar. 26, l97l now US. Pat. No. 3,726,924, in-thenames of Leimgruber and Wick. v

BACKGROUND OF THE INVENTION In recent years, growing interest inattempts to synthesize natural products, particularly those in thealkaloid family, has accentuated the need for a facile and efficientprocess for the methylenation of catechols.

In the past, the preparation of methylenedioxy compounds has beenaccomplished following procedures such as that disclosed by W. Bonthroneand J. W.-Cornforth in Journal of the Chemical Society, 1202 (1969). TheBonthrone and Cornforth procedure involves the preparation ofl,2-methylenedioxy compounds by treating catechols with sodium hydroxideand methylene chloride in dimethylsulfoxide at 125-l30C. forapproximately 3 hours The relatively harsh reaction conditions limit theusefulness of procedures of this type.

We have now found that by carrying out the reaction between the catecholstarting material and methylene chloride in the presence of a selectedstrong base, the desired l,2-methylenedioxy compounds can be obtained ingood yields, usually between 70-90 percent, using distinctly lowertemperatures and simplified reaction and isolation procedures.

DETAILED DEsCRIPTIo oF THE INVENTION selected a CHgClz OH strong base 0In a preferred aspect of the present invention, the catechol startingmaterials are substituted benzene derivatives, i.e. compounds of theformula I HO R1 wherein R R and R independently signify hydrogen, loweralkyl, or lower alkoxy so that by following the instant proce'ssthereare obtained compounds of the formula I wherein R,-R are as describedabove.

In another preferred aspect of the present invention, the instantprocess can be employed in the preparation of .heterocyclic ring systemssuch. as the isoquinoline, benzazepine, benzazocine, and benzodiazocinesystems. In a particularly preferred aspect, 6,7-dihydroxyisoquinolinecompounds are employed as the starting materials so that by followingthe instant process there are obtained 6,7-methylenedioxyisoquinolines.

ln effecting the methylenation of catechols by the instant process, thecatechol starting materials are reacted with methylene chloride in thepresence of selected strong bases. The successful operation of thereaction is due largely to the special properties of the strong basesemployed. Suitable strong bases for the purposes of the presentinvention include tris(dialkylamino)-methanes and aminal esters. Thetris( dialkylamino)-methanes useful for the purpose may be depicted bythe following formula wherein R, through R independently are loweralkyl;

or R and R R and R orR and R taken together with their attached nitrogenatom form a saturated 5- or 6-=membered heterocyclic ring selected fromthe group consisting of pyrrolidyl and piperidyl.

3 wherein R through R signify lower alkyl. The preferred animal estersof formula IV are bis(dimethylamino)-t-butoxymethane andbis(dimethylamino)= methoxy methane.

The methylenation of the catechol starting materials is expedientlyeffected at temperatures above room temperature, preferably at thereflux temperature of methylene chloride. The preferred reactiontemperature can be maintained by keeping the bath temperature betweenabout 40 to about 60C. The reaction time is not critical but ispreferably sufficient to enable completion of the reaction, usually.from six to twentyfour hours. lt is also preferable to effect themethylenation reactions under nitrogen atmosphere using dry methylenechloride.

The tris(dimethylamino)methane employed as one of the preferred stongbases in effecting the instant process may be prepared by treating thereadily available dimethylformamide dimethylacetal with excessdimethylamine in the presence of a select acidic catalyst. Thispreparative route can be depicted by the following reaction scheme:

I CH

H,,CN OCH,, Hl\\ C CH3 H l OCH;

l acid catalyst (lfH CH H CN N--CH N H C CH Only select acidic catalystscan bring about this conversion since both the starting materials andthe end products are subject to rapid hydrolysis and since thedimethylformamide dimethylacetal is a powerful alkylating agent. Thisthe acidic catalyst employed must be one that will not be de-activated,as by akylation, under the reaction conditions employed. Suitable acidiccatalysts for this purpose include, for example, sterically hinderedphenols, e.g. those bearing bulky alkyl groups in the positions orthotothe phenol groups, such as 2,6- di-t-butylphenol,2,4,6-tri-t-butylphenol, and the like; with 2,4,6-tri-t-butylphenolbeing the preferred acidic catalyst. 1

The above described process for preparing tris( dimethylamino)methane isnovel and as such forms a part of the present invention.

As used throughout this disclosure, the term lower alkyl denotes bothstraight and branced chain hydrocarbon groups having from 1 to 7 carbonatoms, such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl, and thelike. The term lower alkoxy denotes a -O lower alkyl group wherein thelower alkyl moiety is as described above.

The following examples further illustrate the invention. Alltemperatures are given in degrees centigrade and all methylenationreactions were carried out under nitrogen atmosphere using dryingmethylene chloride.

4 EXAMPLE. 1

Preparation of bis(dimethy1amino)-tert.'butoxymethane 219.2 g. (3 mole)N,N-dimethylformamidej (freshly distilled from BaO) and 285.2 ml. (378.3g; 3 mole) dimethyl sulfate (distilled) was combined and stirredmechanically. The temperature of the exothermic reaction was maintainedbetween 40 and 55by means of a cold water bath. When the exothermicreaction had subsided, the colorless (or faintly yellow) liquid washeated at for 1 /2 hours.

The resulting oil was added dropwise over 1 /2 hours to a solution of217 g. (4.82 mole) dimethylamine in 1400 ml. dry benzene under vigorousagitation at room temperature. The two phase mixture was then heated atreflux for 1 /2 hours with stirring using a tight seal to avoid loss ofdimethylamine at reflux and left at room temperature overnight. Theupper layer (benzene) was syphoned off, 250 ml. dry ether added to theremaining yellowish oil, stirred for 10 minutes and the upper A mole)potassium tert.-butoxide was added with stirring at such a rate thatmoderate reflux resulted. After all of the alkoxide had been added, thereaction mixture'was heated at reflux for one hour, cooled to roomtemperature and filtered through a sintered glass funnel (medium). Thesintered solids were washed with four i i 7 ml. portions of dry ether,all filtrates combined and the solvent removed under vacuum (not toexceed 20 mm) on the rotary evaporator at a bath temperature of Theremaining turbid liquid was distilled under high I,

vacuum to give bis(dimethylamino)-tert.-butoxymee thane as a colorlessliquid, b.p. 32-35/2.7 mm (bath 43-46).

EXAMPLE 2 Preparation of tris(dimethylamino )rnethane' A mixture of 88g. (0.71 mole) of N,N-dimethylfor-" mamide dimethylacetal and 400 mg.(1.53 mmole) of 2,4,6-tri-t-butylphenol was placed in a 250 ml. 3-neckround bottom flask which was lowered into an oil bath that was kept at astarting temperature of [17C. A,

constant stream of dimethylamine, dried over potassium hydroxidepellets, was passed through the fritted gas inlet at such a rate thatthe temperature of the distillation head at no time exceeded 45. As thereaction. proceeded by removal of methanol, the oil bath tem- 1 peraturewas gradually raised from 1 17 to thus causing a gradual increase of thereaction temperature, from initially 85 to 125l28. After 26 hours, whena substantial portion of the starting acetal was converted totris-(dimethylamino)methane, the oil bath was removed and, aftercooling, the flask was disconnected.

Its content was then flash-distilled at 6 mmHg intoa dry ice-cooledreceiver.

The volatile products were fractionated at 22 mmHg I through a mmVigreux column. The fraction show 7 ing a boiling point of 61-65 at 22mmHg contained 1 the above-named product.

EXAMPLE 3 Preparation of tris( pyrrolidino)methane a. FromN,N-dimethylformamide dimethyl acetal 24.7 g. of 96.5%N,N-dimethylformamide dimethyl acetal (0.2 mol) in 200 g. (9.8 moles) ofpyrrolidine freshly distilled over KOH was kept at reflux for 48 hours(bath temperature l20l40). The methanol formed during the reaction wasremoved constantly through a distillation head connected to the top of areflux condenser kept at 75. The excess pyrrolidine was then distilledoff at atmospheric pressure and the residual yellow liquid distilledunder reduced pressure to give, after a forerun,tris(pyrrolidino)methane as a yellowish liquid, b.p. 122-124l3 mm.

b. From tris(dimethylamino)methane 14.5 g. mmol) oftris(dimethylamino)methane and 50 g. (70 mmol) of pyrrolidine were keptat reflux for 1 hour. The excess pyrrolidine was removed by distillationat atmospheric pressure. Distillation of the residue under reducedpressure gave, after a forerun, tris(- pyrrolidino)methane as acolorless liquid, b.p. 103-104/O.4 mm.

EXAMPLE 4 Preparation of tris(piperidino)methane 134 g. of 89% pureN,N-dimethylformamide dimethyl acetal (1 mol), 595 g. (7 mol) ofpiperidine (distilled over KOH) and 200 ml. of DMF were heated at refluxfor 8 hours with constant removal of the methanol formed. The excesspiperidine was distilled off under aspirator pressure and the residuedistilled under high vacuum to yield, after a forerun, tris(-piperidino)methane as a colorless liquid, b.p. l29--l34/O.5 mm whichsolidified on standing, m.p. 60-65.

EXAMPLE 5 Preparation of 1,2-methy1enedioxybenzene a. Withbis(dimethylamino)-t-butoxymethane 3.0 g. (27 mmol) of catechol in 80ml. of methylene chloride was added dropwise over a period of 10 minutesto 15.5 g. (89 mmol) of bis(dimethylamino)-tbutoxymethane which had beenprewarmed to 60. After the addition (1 hour) the clear mixture was keptat 60 for further 6 hours during which time the methylene chloride wasrefluxing. The reaction material was taken up in ethyl acetate washedwith 2N sodium hydroxide and brine. The residual liquid on removal ofthe solvent was distilled in a Kugelrohr at 84-86/16 mm to givel,Z-methylenedioxybenzene.

b. With tris(dimethylamino)methane 2.2 g. mmol) of catechol in 75 ml. ofmethylene chloride was added dropwise over a period of 10 minutes to 8.7g. (60 mmol) of tris(dimethylamino)methane, preheated at 55. Stirringand warming was continued for 17 hours, after which time the reactionmixture was diluted with 200 ml. methylene chloride and washed with 1Nhydrochloric acid (3 times), 1N sodium hydroxide 1 time) and water 1time). The liquid residue obtained on evaporation of the solvent wasdistilled in a Kugelrohr at 85/15 mm to give l,2- methylenedioxybenzene.

EXAMPLE 6 Preparation of 3,4-methylenedioxytoluene 3.1 g. (25 mmol) of4-methylcatechol in 12 ml. of methylene chloride was added at roomtemperature over 'a periodof 2 hours to 9.57 g. (55 mmol)bis(dimethylamino) t-butoxymethane in 50 ml. of dry methy lene chlorideand the mixture kept at reflux for 6 /2 hours. After standing at roomtemperature overnight, the solvent was taken off, the residue taken upin ethyl acetate, the solution extracted twice with 2N sodium hydroxide,washed three times with brine and dried over sodium sulfate. Removal ofthe solvent and Kugelrohr distillation of the residual brownish oil gavecolorless 3,4-methylenedioxytoluene, b.p. 8792l22 mm.

EXAMPLE 7 Preparation of 4,5-methy1enedioxyl ,2-xy1ene a. Withbis(dimethylamino)-t-butoxymethane I To 574 g. (33 mmol) ofbis(dimethylamino)-tbutoxymethane, stirred magnetically under nitrogenatmosphere at 55, 1.38 g. (10 mmol) of 4,5-dimethylcatechol in 40 ml. ofdry methylene chloride was added over a period of 10 minutes and theresulting reaction mixture kept at reflux (bath temperature 55) for 21hours. Evaporation of the solvent and excess reagent under reducedpressure gave an orange colored solid which. was stirred with 100 ml. ofether for 30 minutes, filtered and the filtrate taken to dryness.Kugelrohr distillation of the solid residue at 90/2.5 mm gave colorlesscrystalline 4,5-methy1enedioxy-l,2-xy1ene, m.p. 4748. I

b. With tris(dimethylamino)methane As described uner (a) 8.6 g. of amixture of 55% tris- (dimethylamino)methane 32.6 mmol) and 45% DMF, and1.38 g. (10 mmol) of 4,5-dimethylcatechol in 40 ml. methylene chloridegave, after 21 hours, 4,5

ride, filtered and, after removal of the solvent, distilled in aKugelrohr to yield 4,5-methy1enedioxy-l ,2-xy1ene.

c1. With tris(piperidino)methane As described under (c) 3.2 g. (12 mmol)of tris(- piperidino)-methane and 522 mg. (4 mmol) of 4,5-dimethylcatechol in 25 ml. methylene chloride gave, after 18 hours,crystalline 4,5-methy1enedioxy-1,2- xylene.

EXAMPLE 8 Preparation of 2,3-methy1enedioxyanisole The reaction wascarried out with 23 g. (132 mmol) of bis(dimethylamino)-t-butoxymethaneand 5.6 g. (40 mmol) of 3-methoxycatechol in m1. of methylene chloride.After 20 hours the reaction mixture was taken to dryness under reducedpressure and the residue distilled at 78-82/2mm to yield crystalline2,3- methylenedioxyanisole.

EXAMPLE 9 Preparation of l-( 4-chlorophenethyl)-2-pivaloyl-6,7-methylenedioxyl,2,3,4-tetrahydroisoquinoline To 1.0 g.(2.6 mmol) of l-(4-chlorophenethyl)-2- pivaloyl-6,7-dihydroxy-l,2,3,4-tetrahydroisoquinoline suspended in ml. of dry methylenechloride, was added 1.73 ml. (1.47 g., 8.43 mmol) ofbis(dimethylamino)-t-butoxymethane causing the formation of a cleargreen solution which was kept at 50 under nitrogen for 6 hours. Thereaction mixture was taken up in ethyl acetate, washed twice with 1Nsodium hydroxide, once with 1N hydrochloric acid and twice with brineand dried over sodium sulfate. The residual heavy oil obtained afterremoval of the solvent was chromatographed on 50 g. of silica gel.Benzene/ether 9:1 and then 1:1 eluted the desired product as a colorlessoil. I-( 4-Chlorophenethyl )-2-pivaloyl-6,7-methylenedioxy-l,2,3,4-tetrahydroisoquinoline crystallized from ether/heptane, m.p.97-99.

The starting material is prepared as follows:

4.0 g. (108 mmol) of sodium borohydride was added portionwise to 10 g.(30.1 mmol) ofl-(4-chlorophenethyl)-6,7-dimethoxy-3,4-dihydroisoquinoline in 125 ml.of methanol under stirring. During the addition, the reactiontemperature was maintained below 30 by means of a cold water bath. Thereaction mixture was stirred overnight, then taken down to drynessunder. reduced pressure, and the resulting residue dissolved inchloroform. The chloroform solution was washed with dilute ammonia,water and dried over sodium sulfate. Removal of the solvent gavel-(4-chlorophenethyl) 6,7-dimethoXy-l,2,3,4-tetrahydroisoquinoline as acrystalline product, which was recrystallized from ether, m.p. 6364.

6.7 g. (19.8 mmol) of l-(4-chlorophenethyl)-6,7- dimethoxy-l,2,3,4-tetrahydroisoquinoline in 200 ml. of 48% hydrobromic acid waskept at 125 for 7 hours. On cooling, the hydrobromide crystallized andwas collected. A sample was recrystallized from ethanol, m.p. 226-232.

980 mg. (3.23 mmol) of the free base of the hydrobromide (generated bytreatment of the hydrobromide with dilute ammonia) was added to asolution of 1.363 g. (l 1.31 mmol) of pivaloyl chloride in ml. ofmethylene chloride. Gradual dissolution of the suspension was observedwhen 358 mg. (3.23 mmol) of triethylamine in 10 ml. of methylenechloride was added dropwise. After 2 hours TLC analysis showedconsumption of all starting material. The resulting reaction mixture wasstirred at room temperature for two days in 10 ml. of 1N sodiumbicarbonate, taken up in ethyl acetate washed with brine, dried and thesolvent evaporated to yieldl-(4-chlorophenethyl)Q-pivaloyl-6,7-dihydroxy-'l,2,3,4-tetrahydroisoquinoline, recrystallized from ethyl acetate, m.p.209-2l0.

We claim:

1. A process for the methylenation of catechols corn- 7 prising the stepof reacting a catechol of the formula.

wherein R R and R are selected from the group consisting of hydrogen C Clower alkyl and lower alkg oxy with methylene chloride in the presenceof a strong base selected from the group consisting of tris(dime- Ithylamino) methane, tris(pyrrolidino)methane, tris(lpiperidino)methane,bis)dimethylamino)-t-butoxymethane andbis(dimethylamino)-methoxymethane.-

2. A process for the preparation of an aromatic com- 7 pound of theformula wherein R R and R are selected from the group consisting ofhydrogen C,C lower alkyl and lower alkoxy comprising the step ofreacting an aromatic compound of the formula piperidino)methane,bis(dimethylamino)-t-butoxymethane and bis(dimethylamino)-methoxymethane.

=l l l

1. A PROCESS FOR THE METHYLENATION OF CATECHOLS COMPRISING THE STEP OFREACTING A CATECHOL OF THE FORMULA
 2. A process for the preparation ofan aromatic compound of the formula